1. Field of the Invention
The present invention relates to a pharmaceutical composition for inhibiting angiogenesis comprising an isolated peptide comprising the heparin-binding domain of insulin-like growth factor-binding protein-5 (IGFBP-5), a method for inhibiting angiogenesis using the peptide, a pharmaceutical composition for the prevention or treatment of cancer comprising the peptide, a method for treating cancer using the peptide, a novel angiogenesis-inhibiting peptide derived from heparin-binding domain of IGFBP-5, a polynucleotide encoding the peptide, an expression vector comprising the polynucleotide and a transformant comprising the vector.
2. Description of the Prior Art
Insulin-like growth factor-binding protein-5 (IGFBP-5), a member of the IGF (insulin-like growth factor) binding protein family, is known to play an important role in various cellular functions, including cell proliferation. IGFBP-5 is localized to the nucleus due to its NLS (nuclear localization signal) and is also secreted extracellularly. However, studies on the functions of IGFBP-5 in the nucleus and the functions of extracellularly secreted IGFBP-5 have not yet been sufficient. It was recently reported that IGFBP-5 functions as a transactivator in the nucleus.
Specifically, IGFBP-5 consists largely of three domains: N-terminal domain, L-domain, and C-terminal domain. An IGF-binding site is located in the N-terminal domain, and an NLS is located in the C-terminal domain. In addition, a heparin-binding site is located in both the L-domain and the C-terminal domain. The glycosylation and phosphorylation of IGFBP-5 are known to inhibit the heparin binding of IGFBP-5, but the exact biological significance of the glycosylation and phosphorylation has not yet been established.
As is known in the art, IGFBP-5 modulates the functions of IGF-I and IGF-II by inhibiting the binding of IGF-I or IGF-II to their receptors, but IGF-independent functions of IGFBP-5 were also reported. In addition, in the results of studies performed using IGFBP-5 transgenic mice and knockout mice, IGFBP-5 transgenic mice showed high neonatal mortality, growth inhibition and delayed muscle development. Further, IGFBP-5 transgenic female mice showed sterility and premature cell death in the mammary glands. In addition, IGFBP-5 knockout mice demonstrated delayed mammary gland involution. Such results suggest that IGFBP-5 can induce apoptosis.
Angiogenesis is the process by which new blood vessels are formed from existing blood vessels and an elaborate network is formed by way of a variety of complex mechanisms. Typical known examples include a mechanism by which an angiogenic factor acts on the receptor of vascular endothelial cells to induce the proliferation of vascular endothelial cells, a mechanism that is involved in the migration of vascular endothelial cells by secretion of matrix metalloproteinase, a mechanism that is involved in the adhesion of vascular endothelial cells, and the like. Angiogenesis is essential for normal development, that is, fetal development, reproductive cycles, growth, and wound healing, and is also involved in the progression of diseases such as cancer and diabetic retinopathy.
For the treatment of angiogenesis-related diseases such as cancer, studies on the inhibition of angiogenesis have been actively conducted. Particularly, there have been studies on methods of administering antagonists in order to inhibit the activities of VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) known to be potent angiogenesis inducers in angiogenic processes, and methods of controlling the expression of integrin in vascular endothelial cells in order to inhibit the metastasis of cancer cells. In particular, VEGF is the most potent angiogenesis inducer that shows various biological activities by binding to its two receptors (VEGFR1 and VEGFR2) present on the surface of endothelial cells and plays a pivotal role in both vasculogenesis and angiogenesis. Thus, studies on drugs that inhibit angiogenesis by reducing the expression and signaling of VEGF have been actively conducted.